BACKGROUND We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease. METHODS We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P = 0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P = 0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P = 0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P = 0.057 for interaction). CONCLUSIONS The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)

Background Persons with type 2 diabetes (T2D) are at risk for cognitive impairment and brain atrophy. The ACCORD Memory in Diabetes (MIND) Study investigated whether persons randomized to an intensive glycaemic therapeutic strategy targeting HbA1c to <6% had better cognitive function and a larger brain volume at 40 months than persons randomized to a standard strategy targeting HbA1c to 7%–7.9%. Methods ACCORD MIND was a double 2×2 factorial parallel group randomised trial conducted in 52 clinical sites in North America. Participants [age 55 – <80 years] with T2D, high HbA1c concentrations (>7.5%), and at high risk for cardiovascular events were randomised to treatment groups using a centralized web-based system. Clinic staff and participants were not blinded to treatment arm. The cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, was assessed at baseline, 20 and 40 months. Total brain volume (TBV), the primary brain structure outcome, was assessed with MRI at baseline and 40 months in a sub-set of 632 participants. All participants with follow-up data were included in the primary analyses. In February, 2008, increased mortality risk led to the termination of the intensive therapy and transition of those participants to standard glycaemic treatment. Results Randomised patients (n=2977; mean age 62.3 years) were consecutively enrolled; the final analysis included 1358 intensive and 1416 standard arm participants with a 20 or 40 month DSST score. Of the 614 with a baseline MRI, 230 intensive and 273 standard therapy participants were included in the analysis. There was no treatment difference in the DSST score. The intensive group had a greater TBV than the standard group (difference, 4.62; 95% CI 2.0 to7.3 cm3; p=0.0007). Interpretation Although significant differences in TBV favored the intensive therapy, cognitive outcomes were not different. Combined with the unfavorable effects on other ACCORD outcomes, MIND findings do not support using intensive therapy to reduce the adverse effects of diabetes on the brain in patients similar to MIND participants. (ClinicalTrials.gov number, NCT00182910).

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OBJECTIVE -Diabetes is associated with cognitive decline and dementia. However, the relationship between the degree of hyperglycemia and cognitive status remains unclear. This was explored using baseline cognitive measures collected in the ongoing Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESULTS -A statistically significant age-adjusted association was observed between the A1C level and the score on all four cognitive tests. Specifically, a 1% higher A1C value was associated with a significant 1.75-point lower DSST score (95% CI Ϫ1.22 to Ϫ2.28; P Ͻ 0.0001), a 0.20-point lower MMSE score (Ϫ0.11 to Ϫ0.28; P Ͻ 0.0001), a 0.11-point lower memory score (Ϫ0.02 to Ϫ0.19, P ϭ 0.0142), and a worse score (i.e., 0.75 s more) on the Stroop Test (1.31-0.19, P ϭ 0.0094). The association between the DSST score and A1C persisted in all multiple linear regression models. FPG was not associated with test performance. RESEARCH DESIGN AND METHODSCONCLUSIONS -Higher A1C levels are associated with lower cognitive function in individuals with diabetes. The effect of glucose lowering on cognitive function will be determined by the ongoing ACCORD-MIND trial. Diabetes Care 32:221-226, 2009M ild cognitive impairment represents an important phase on the path from normal cognitive function to dementia. Affected individuals have measurable deficits in cognitive function that may affect their ability to master complex behaviors such as those required for diabetes self-care (1). Moreover, because mild cognitive impairment is more common than frank dementia, its potential population health impact is high. For example, the prevalence of mild cognitive impairment (i.e., predementia) in the Cardiovascular Health Study was 19% in individuals aged Ͼ65 years and 29% in those aged Ͼ85 years.Diabetes is associated with premature mortality and is a risk factor for mild cognitive impairment and both vascular dementia (2-5) and Alzheimer's disease (2,6 -8). Indeed, individuals with diabetes are ϳ1.5 times more likely to experience cognitive decline and frank dementia than individuals without diabetes (9). Precise reasons for the high morbidity and mortality of diabetes remain unknown; however, many studies have demonstrated a link between many of the consequences of diabetes and the degree of hyperglycemia as measured by the A1C or glucose level. Emerging evidence suggests that a relationship between measures of short-term glucose control and cognitive function also exists. For example, in a cross-sectional analysis of 378 high-functioning individuals with diabetes, higher A1C but not fasting plasma glucose (FPG) levels were consistently associated with lower scores on two cogni-

OBJECTIVESelf-management of type 2 diabetes including avoidance of hypoglycemia is complex, but the impact of cognition on safe self-management is not well understood. This study aimed to assess the effect of baseline cognitive function and cognitive decline on subsequent risk of severe hypoglycemia and to assess the effect of different glycemic strategies on these relationships.RESEARCH DESIGN AND METHODSProspective cohort analysis of data from the ACCORD trial included 2,956 adults aged ≥55 years with type 2 diabetes and additional cardiovascular risk factors. Cognitive tests (Digit Symbol Substitution Test [DSST], Rey Auditory Verbal Learning Test, Stroop Test, and Mini Mental Status Examination) were conducted at baseline and 20 months. Study outcomes were incident confirmed severe hypoglycemia requiring medical assistance (HMA) and hypoglycemia requiring any assistance (HAA).RESULTSAfter a median 3.25-year follow-up, a 5-point-poorer baseline score on the DSST was predictive of a first episode of HMA (hazard ratio 1.13 [95% CI 1.08–1.18]). Analyses of the other cognitive tests and of HAA were consistent with the DSST results. Cognitive decline over 20 months increased the risk of subsequent hypoglycemia to a greater extent in those with lower baseline cognitive function (Pinteraction = 0.037). Randomization to an intensive versus standard glycemic strategy had no impact on the relationship between cognitive function and the risk of severe hypoglycemia.CONCLUSIONSPoor cognitive function increases the risk of severe hypoglycemia in patients with type 2 diabetes. Clinicians should consider cognitive function in assessing and guiding their patients regarding safe diabetes self-management regardless of their glycemic targets.